Our data indicate that vesicular stomatitis virus, VSV, is a potent agent in the eradication of malignant cells. The mechanisms underlining VSV oncolytic activity may involve flaws in the innate immune system, regulating type I interferon (IFN) production that controls the induction of anti-viral genes. We have exploited this defect by developing VSV that expresses innate immune genes such as IFN?. This virus maintains oncolytic activity in malignant cells due to existing cellular defects that prevent IFN antiviral function. However, the virus is extremely attenuated since viral produced exogenous IFN prevents viral replication in normal cells. Based on these findings, we have now generated a new VSV vectors that express IFN? as well as miR124 target sequences in the 3-UTR region of their viral genes. MiR124 is expressed in normal neuronal tissue, but not neuronal derived cancer tissue such as glioblastoma. Our preliminary data indicates that VSV-miR124-IFN is even more attenuated than VSV-IFN because prevalent miRNAs suppress viral replication in the central nervous system. The combination of using type I IFN as well as miRNAs in VSV therapeutics has led to the development of a more specific cancer virus that may be useful for the treatment of metastatic disease as well as glioblastoma. We thus propose two aims. First, we will evaluate the use of VSV-miR124-IFN as a systemic treatment against metastatic disease including melanoma and breast adenocarcinoma. Second, we will evaluate the use of VSV-miR124-IFN as a potential therapeutic to treat glioblastoma.